Senescence of POMC neurons is believed to contribute to the etiology of age-related obesity. As we have identified tanycytes to express POMC in the adult brain and recent evidence indicates that tanycytes have stem cell-like properties and can serve as progenitor cells for hypothalamic neurons, we hypothesize that tanycytes are capable of differentiating into POMC neurons in the mediobasal hypothalamus and potentially could restore failing POMC neurons in the aging brain. To begin to test this hypothesis, we propose to use the R21 exploratory mechanism to determine whether tanycytes can generate POMC neurons in the postnatal brain and integrate into the feeding-related circuitry. To perform these studies, a POMC null transgenic mouse model, ArcPomcfneo/fneoKO, which have an obese phenotype due to the loss of POMC in the mediobasal hypothalamus, will be crossed with RaxCreERT2 mice in which Cre-recombinase is expressed exclusively in tanycytes in response to tamoxifen. Therefore, all POMC neurons observed in the offspring of the resulting ArcPomcRaxRE mice can only be derived from tanycytes. We will determine whether these mice show evidence for improvement in metabolic parameters and obesity when tanycyte POMC is reactivated at postnatal day 4 vs. postnatal day 28 over a 4 month observation period. Included in the analysis will be growth, body weight, food intake, body composition, energy balance, glucose homeostasis and thyroid function. At the end of the observation period, animals will be euthanized to determine the number and location of activated POMC neurons in the mediobasal hypothalamus compared to intact and null POMC controls, and whether they migrate to their natural loci in the mediobasal hypothalamus and integrate into the feeding-related circuitry. Tanycyte-derived POMC neurons will also be phenotyped with respect to their expression of neurotransmitters and responsiveness to leptin. These studies are expected to expand the understanding of POMC system neurobiology in the hypothalamic arcuate nucleus and provide new and novel insights into ways the melanocortin system could be regulated to treat obesity and metabolic disorders associated with aging.